1. Field of the Invention
The present invention relates to the use of compounds which are inhibitors of nitric oxide synthase (NOS). The present invention also includes within its scope methods of treatment where nitric oxide is involved in the biological functions of the human body,e.g. hypotension, inflammation, the damage due to inflammation, acute and/or chronic pain, neuronal disorders such as stoke, memory disorders,and depression, autoimmune diseases, including allograft rejection,diabetes, septic and endotoxic shock and the like.
2.Background of the Art
Nitric oxide is an important component of endothelium derived relaxing factors (EDRFs). EDRFs have been shown to be involve in the regulation of blood flow and vascular resistance. In addition to the vascular endothelium, macrophages have also been reported to produce nitric oxide in the body which is a component of their cell killing and/or cytostatic function. Nitric oxide is produced in mammalian cells by nitric oxide synthase (NOS) by conversion of L-arginine to citrulline Moncada, S., Palmer,R. M. J., and Higgs, E. A. (1991) Pharm. Rev. 43, 109-142.; Nathan, C. (1992) FASEB J. 6, 3051-3064; Jacob, T. D., Morrell, M. K., Manzi, S., Ochoa, J. B., Verdile, V., Udekwu, A. O., Berceli, S. A., Simmons, R. L., and Peitzman, A. B. (1992) in NitricOxide: Implications for Drug Research, P. 28, IBC, South Natick, Mass.; Langrehr, J. M., Murase, N., Markus, P. M., Cai, X., Neuhaus, P., Schraut, W., Simmons, R. L., and Hoffinan, R. A. (1992) J. Clin. Invest 90, 679-683; Corbett, J. A., Tilton, R. G., Chang, K., Hasan, K. S., Ido, Y., Wang, J. L., Sweetland, M. A., Lancaster, J. R. Jr., Williamson, J. R., and McDaniel, M. L. (1992) Diabetes 41, 552-556; Griess, P. (1879) Chem. Ber. 12 426.
There are three distinct isoforms of human NOS, neuronal (bNOS), endothelial (eNOS) and inducible (iNOS).
In general eNOS is constitutively expressed and produces reletively low levels of NO. Activity of eNOS is dependent on Ca.sup.2+ influx. eNOS is found in vascular smooth muscle cells which is not identical to the form of enzyme found in neurons. Formation of NO by the eNOS in vascular endothelial cells is believed to play a role in regulating blood pressure by relaxing muscles and allowing the vessel to dialate, which lower the blood pressure Pollock, J. S., Forstermann, U., Mitchell, J. A., Warner, T. D., Schmidt, H. H. H. W., Nakane, M. and Murad, F. (1991) Proc. Natl. Acad. Sci. USA 88, 10480-10484; Lamas, S., Marsden, P. A., Li, G. K., Tempst, P. and Michel, T. (1992) Proc. Natl. Acad. Sci. USA 89, 7773-7777.
Disruption of the neuronal NOS (second isoform of NOS) gene causes no histological abnormalities in the central nervous system Huang, P. L., Dawson, T. M., bredt, D. S., Snyder, S. H. and Fishman, M. C. (1993) Cell 75, 1273-1286.
iNOS is not dependent on elevated Ca.sup.2+ concentration and generally expressed only after induction by certain cytokines or by bacterial lipopolsaccharide (LPS) Wei, X.sub.-- q., Charles, I. G., Smith, A., Ure, J., Feng, G. .sub.-- j., Huang, F. .sub.-- p., Xu, D., Muller, W., Moncada, S. and Liew, F. Y. (1995) Nature (London) 375, 408-411.
It is thought that in sepsis or cytokine-induced shock, excess production of nitric oxide by iNOS plays an important role in life-threatening hypotension. Evidence for this has come from observations that serum levels of NO oxidation products are elevated in animals and humans undergoing septic shock and from in vivo studies with NOS inhibitors Goode, H. F., Howdle, P. D., Walker, B. E. and Webster, N. R. (1995) Clin. Sci. 88, 131-133; Barthlen, W., Stadler, J., Lehn, N. L., Miethke, T., Bartles, H. and Siewert, J. R., (1994) Shock 2, 398-401; Cunha, F. Q., Assreuy, J., Mass, D. W., Rees, D., Leal L. M. C., Moncada, S. and Carrier, M. (1994) Immu. 81, 211-215. Furthermore, it has been postulated that excess production of nitric oxide by iNOS is a factor in the unresponsiveness to pressor agents such as alpha.sub.1 -adrenergic agonists employed in the treatment of septic or cytokine-induced shock patients.
We are now describing a new class of compounds useful as inhibitors of iNOS. See for example the paper presented by Mosby et al. reported in J. Org. Chem., 24, 374-380 (1959) entitiled "Reactions of 2,3-dichloro-1,4-naphthoquinone with 2,Aminopyridine and Related Amines", Offenlegungsschrift DE 3926747 A1 entitled "1,2-Naphthochinone enthalende fungizide Mittel", Asahi et al. Chem. Pharm. Bull., 32, 3093-3099 (1984), and Carroll et al. J. Heterocycl. Chem. 7, 297-306 (1970). These compounds are described below.